563 hyperhomocysteinemia, or dysregulation of the Ca–phosphate–PTH axis, are risk factors primarily present in CKD patients Furthermore, there are a number of potential iatrogenic or treatment related[.]
30 The Cardiovascular Status of Pediatric Dialysis Patients hyperhomocysteinemia, or dysregulation of the Ca–phosphate–PTH axis, are risk factors primarily present in CKD patients Furthermore, there are a number of potential iatrogenic or treatment-related risk factors such as exposure to a high Ca load from dialysate, calcium-based phosphate binders, and vitamin D therapy; advanced glycation end-products, metabolic acidosis, and warfarin therapy can all contribute to the pro-calcific uremic milieu The key factors are described in detail below Dysregulations in the Ca–P–PTH axis (see also Chap 29) are central to the vascular damage and calcification in CKD patients Phosphate has probably the best described spectrum of toxicity of all molecules that circulate in excess in CKD. Decreased renal P excretion plays a major role in the onset of hyperparathyroidism Furthermore, plasma P levels are positively and independently correlated with an increasing risk of death from CVD [45] Phosphate is filtered at the glomerulus and reabsorbed in the proximal tubules, with approximately 85% of the filtered phosphate reabsorbed via the sodium-phosphate co-transporter IIa located in the proximal tubular brush border membranes It would be expected, therefore, that CKD would result in hyperphosphatemia However, we now know that compensatory mechanisms in the form of increased fibroblast growth factor-23 (FGF-23) levels act to preserve a normal plasma P in early CKD [46] FGF-23 is a hormone produced by the osteocyte, and together with its obligate co-receptor, Klotho, results in a negative phosphate balance, by decreasing renal tubular phosphate reabsorption and suppressing renal 1-α hydroxylase, thereby reducing the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D) [46] However, as CKD progresses, there is increasing FGF-23 resistance and P retention occurs, stimulating PTH secretion Studies in adult patients have conclusively identified that plasma phosphate is an independent predictor of mortality in CKD. This link was first demonstrated in adult HD patients: as serum phosphate levels increased above 5.6 mg/dL (= 1.8 mmol/L), the hazards ratio for mortality increased by 6% for every 1 mg/dL (= 0.3 mmol/L) increase in serum phosphate [45] Hyperphosphatemia has also been shown to be an 563 independent risk factor for death in the pre- dialysis population [47, 48] Data from >26,000 adult dialysis patients have shown that in over 80% of patients, at least one biochemical variable was uncontrolled Pediatric studies have similarly shown that plasma phosphate adversely affects cIMT, coronary calcification, and left ventricular mass, and these studies are discussed in detail below Several in vitro studies using vascular smooth muscle cell (VSMC) cultures and intact human vessels have shown the direct causal role of P in inducing and promoting vascular calcification [49, 50], and are discussed below CKD patients are thought to be in a net positive Ca balance as a result of iatrogenic Ca loading from Ca-based phosphate binders, vitamin D therapy, dialysate Ca, and reduced or absent Ca removal via the kidneys In the above study by Block et al., patients with high calcium levels and PTH > 300 pg/dl were consistently associated with a higher risk of death or cardiac dysfunction [51] Current guidelines state that hypercalcemia may be harmful in all GFR categories of CKD and call for restriction in the use of calcium-containing phosphate binders [52] Current K/DOQI guidelines recommend a maximum elemental calcium load of 2000 mg/day, including calciumcontaining medication (maximum 1500 mg/day) and a maximum dialysate calcium concentration of 1.25 mmol/L (to avoid intradialytic Ca loading) [53] Ca balance studies during HD have shown that the majority of HD patients are continually experiencing Ca overload Also, the amount of Ca removed during dialysis was independent of the exogenous Ca load from diet or binders [54] These transient increases in Ca that inevitably occur in clinical practice may go unrecorded, but can impact on ectopic calcification, particularly in the setting of high P conditions Clinical studies have reported that the extent of arterial calcification was directly related to the number of episodes of hypercalcemia during the preceding 6 months [55] and in the “Treat-toGoal” study, the Ca-treated group had significantly more hypercalcemic episodes than the sevelamer group [56] Oxidative stress is a major contributor to increased atherosclerosis and cardiovascular 564 R Shroff and M M Mitsnefes morbidity and mortality in CKD. Malnutrition homocysteine through diet or drugs may be parand hypoalbuminemia reduce the antioxidant alleled by a reduction in cardiovascular risk It is defense and increase vulnerability to oxidant presumed that homocysteine exerts a direct toxic injury Retained uremic solutes, such as the effect on the vessel wall, and one small study in advanced glycation end-products (AGE) that are children has shown that folic acid supplementasubstrates of oxidized dialysate components, tion may improve endothelial function with an homocysteine, cysteine, and ß2-microglobulin, increased resistance of LDL to oxidation [70] further contribute to the pro-atherogenic milieu However, several randomized controlled studies in uremia Although dialysis treatment reduces in adults have failed to show a beneficial effect of the concentration of oxidized substrates, amelio- folic acid supplementation, and very high doses rating the oxidant–antioxidant balance, dialysis- of folic acid have recently been linked with an associated factors such as vascular catheters, increased risk of malignancies [71] dialysis membranes, and exposure to dialysate or Anemia (see also Chap 27) is a major uremia- oxidants in HD water, can also induce further related cardiovascular risk factor that is highly pro-atherogenic insults [57] prevalent in children and adolescents with ESRD can be considered a low-grade inflam- advanced CKD. Unlike the other major uremia- matory state Oxidative and carbonyl stress may related risk factors, it appears relatively early in stimulate cells and the endothelium to release the course of CKD. Despite the introduction and IL-6 and other pro-inflammatory cytokines that wide use of recombinant erythropoeisis stimulatare directly linked with the initiation and progres- ing agents (ESAs), anemia remains common sion of atherosclerosis in HD and PD patients Data from the CKiD cohort have demonstrated [58–60] The inflammatory state is often associ- that below a measured GFR of 43 mL/ ated with malnutrition, and the combination is min/1.73 m2, the hemoglobin decreased by 0.3 g/ directly linked with a high risk of atherosclerosis dL for every 5 mL/min/1.73 m2 decrement in [61], often known as the malnutrition-GFR [72] Data from the NAPRTCS registry supinflammation- atherosclerosis (MIA) complex port the finding that anemia is common in pediatThe presence of MIA in a CKD patient is associ- ric CKD patients (increasing from 18.5% in stage ated with a significantly higher mortality rate CKD to 68% in stage pre-dialysis patients); [62] The physiological calcification inhibitor, furthermore, patients with anemia were 55% fetuin-A, is a negative acute phase reactant and more likely to be hospitalized than those with a its production is downregulated in an inflamma- normal hemoglobin level [73] Anemia remains a tory milieu [63]; fetuin-A may be the missing significant risk for both morbidity and mortality link between inflammation and atherosclerosis [74, 75] Data from IPPN demonstrated that 25% [64] Recent studies have shown that vitamin D of patients had hemoglobin levels below target, has a cardioprotective effect, and one of its sev- and low hemoglobin levels were associated with eral beneficial effects on the heart and vascula- low urine output, low serum albumin, high parature may be mediated by its anti-inflammatory thyroid hormone, high ferritin, and the use of bioeffects [65, 66] incompatible PD fluid [76] In this study, anemia Hyperhomocysteinemia is a significant risk and high ESA dose requirements (likely secondfactor for atherosclerosis [67, 68] and has been ary to ESA resistance due to inflammation) indeassociated with increased carotid artery intima- pendently predict mortality Until recently, medial thickness (cIMT) and LVH in children posttransplant anemia has also been under- [60, 69] Folic acid and B vitamins, required for appreciated However, with introduction of more remethylation of homocysteine to methionine, potent immunosuppression therapy, recently are the most important dietary determinants of reported anemia prevalence rates have ranged homocysteine, and daily supplementation typi- from 61% to 86% [75, 77] cally lowers plasma homocysteine levels, but it is Dialysis vintage (the time on dialysis) has unclear whether the decreased plasma levels of been implicated as a predictor of coronary artery 30 The Cardiovascular Status of Pediatric Dialysis Patients calcification in children and young adults (Table 30.2) Coronary calcification can be seen as early as the first decade of life in children on dialysis Dialysis vintage was associated with the presence of calcifications, even in patients who had undergone transplantation (dialysis vintage was calculated as cumulative time on dialysis) [78].This suggests that calcification develops in a time-dependent manner on dialysis, and suggests that there is little or no regression associated with a functioning transplant A recent review article has suggested that there is a strong, albeit insignificant linear association between dialysis vintage and coronary artery calcification (CAC) score across all published studies of CAC in young patients with childhood-onset ESRD, suggesting an exponential effect of dialysis vintage on the development of CAC [79] Surrogate Measures of Cardiovascular Risk in CKD Patients Unlike studies in adult CKD patients where “hard” end points such as death or cardiovascular events are used, pediatric studies must rely on surrogate measures of cardiovascular damage These include cardiac and vascular measures of structure and function, and biomarkers from blood and urine Echocardiography is a gold standard to assess for the presence of LVH or systolic and diastolic dysfunction Measures of structural changes in the vessels include the cIMT (measured by high-resolution ultrasound scan of the common carotid arteries) and direct evidence of CAC on multi-slice CT scan Functional changes in the vasculature can be determined by the pulse wave velocity (PWV) that determines stiffness or loss of compliance in the vessel and distensibility of the common carotid artery measured by ultrasound (Fig. 30.2) Although cIMT, PWV, and CAC have been extensively used in many studies of vascular outcome, there is recent evidence to show that they are not sensitive markers of early vascular damage and must be interpreted with caution [76] In addition, numerous biomarkers of vascular dam- 565 age and future cardiovascular events have been described and some validated against “hard end- points.” In our current state of knowledge, these can best serve as corroborative evidence of vascular injury or predictors of future cardiovascular events, but cannot replace the established vascular measures described above Some of the better defined biomarkers are vitamin D levels (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) [80–82] and FGF-23 [83], the physiological calcification inhibitors (fetuin-A, matrix Gla- protein, and osteoprotegerin) [84], endothelial microparticles, and cardiac troponin levels [85] Left Ventricular Structure and Function As in adults, a number of studies have shown that LVH develops relatively early in the course of CKD in children, and becomes more common as renal function declines Although some small retrospective studies demonstrate regression of LVH with better blood pressure and volume control while on dialysis, others have demonstrated worsening of LVH. Left ventricular hypertrophy is also commonly seen after renal transplantation in children Considering all of the available data, approximately one third of children with CKD stages 2–4 [23, 86, 87] and up to 50–80% of pediatric dialysis patients have LVH [24] The prevalence of LVH has remained stable and quite high over last two decades Data from the Turkish registry of children on maintenance dialysis collected from 2008 to 2013 showed the prevalence of LVH to be 59% [88] Data from IPPN demonstrated the overall LVH prevalence to be 48% In the IPPN prospective analysis, the incidence of LVH developing de novo in patients with normal baseline LV mass was 29%, and the incidence of regression from LVH to normal LV mass was 40% per year [89] Beyond childhood, in the follow- up of 140 adults who developed ESRD before the age of 14 years, the Dutch Late Effects of Renal Insufficiency in Children (LERIC) study has also demonstrated that LVH is common (47% of male and 39% of female patients), as is diastolic dysfunction (13%) [3] Eifinger et al., NDT, 2000 [105] Oh et al., Circulation, 2002 Groothoff et al., JASN, 2002 [106] Litwin et al., JASN, 2005 Mitsnefes et al., JASN, 2005 Goodman et al., NEJM, 2000 Author, journal, year No 44– CKD 2–4 16 – dialysis 55– CKD 2–4 37 – dialysis 34 – transplant cIMT correlated with Dialysis duration Mean serum Ca × PO4 Ca intake from binders Mean calcitriol dose cIMT correlated with Dialysis duration Mean serum Ca × PO4 Ca intake from binders Mean calcitriol dose Stiffness correlated with Mean serum Ca × PO4 Mean PTH levels IMT, distensibility, and stiffness of carotid artery and ECHO Pre-dialysis CKD – 7.1 ± 5.1 years Dialysis – 2.2 ± 2.9 years Transplant-2.8 ± 3.2 years Pre-dialysis CKD –? Dialysis – 1.2 ± 1.3 years (range 0.3–3.7 years) Range 10–20 years CAC and cIMT correlated with ESRD duration Dialysis duration Mean serum Ca × PO4 CAC correlated with PTH levels Hs-CRP Homocysteine levels Hypertension main determinant of abnormal arterial wall properties No biochemical data available Presence of CAC correlated with Age Dialysis duration Mean serum PO4 and Ca × PO4 Ca intake from binders None found Clinical and biochemical correlations Carotid and femoral IMT, wall and lumen cross-sectional areas cIMT, stiffness measures RRT – 18 years Dialysis – 4.5 years Tx (n = 101) – 13.5 years 29 (range 20.7–40.6) (young adults with childhood onset ESRD) 130 29 dialysis CAC + cIMT 5.0 (range 0–22) 27.3 (range 19–39) (young adults with childhood onset ESRD) 39 CAC CAC 26.5 (range 14–39) 16 7 ± 6 (range 0.3–21) Duration of dialysis Vascular (years) measures RRT for 2.5–21 years 19 ± 7 (range 7–30) Mean age (years) 39 No of patients Increased cIMT in dialysis compared with pre-dialysis patients No change in vessel stiffness pre-dialysis, but increased carotid artery stiffness noted in the dialysis group, suggesting that structural changes precede functional abnormalities CAC in 6/16 (37%) patients All children asymptomatic despite high CAC burden 50% of deaths are due to cardiovascular or cerebrovascular causes High prevalence of arteriopathy in young adult survivors of CKD Vascular damage correlates with Ca–PO4 load, hyperparathyroidism, and microinflammation, but not “traditional” risk factors No increase in cIMT compared with controls, but reduced distensibility and increased vascular stiffness parameter in all CKD groups No difference in cIMT or arterial wall stiffness between dialysis and transplant groups Increased cIMT in all CKD groups – significantly greater in dialysis compared with transplant patients Suggest partial reversibility post-Tx Carotid lumen increased post-Tx – possibly as a result of higher BP post-Tx No CAC in any patients 20 years had CAC CAC doubled on follow-up scan at 20 months Key message Table 30.2 Vascular measures and their correlations in pediatric and young adult dialysis patients (in chronological order of publication date) 566 R Shroff and M M Mitsnefes Covic et al., NDT, 2006 Briese et al., NDT, 2006 Civilibal et al., Ped Nephrol, 2006 Shroff et al., JASN, 2007 Civilibal et al., Ped Nephrol, 2007 Poyrazoglu et al., Ped Nephrol, 2007 [111] 10 11 12 5–18 years 14.8 ± 3.8 years 18.0 ± 4.3 years 39 34 15.7 years (range 6.9–22.7 years) 53 85 23.6 years (young adults who developed ESRD at ∼11 years age) 14.1 ± 2.6 years 40 14 4.6 ± 2.9 years 4.8 ± 2.6 years Minimum 6 months; mean 2.2 ± 1.8 years cIMT and ECHO cIMT, endotheliumdependent dilatation, and ECHO cIMT PWV CAC CAC cIMT correlated with Diastolic BP Higher mean serum Ca × PO4 Higher total and LDL cholesterol Higher homocysteine levels Higher mean calcitriol dose cIMT correlated with Mean BP Left ventricular mass index Inversely with PTH (negative correlation) (No data available for phosphate binder or calcitriol dosage) Patients with calcification were Older Longer dialysis duration Increased cIMT Higher mean serum Ca × PO4 Increased Ca intake from binders Increased mean calcitriol dose Presence of CAC correlated with Longer dialysis duration Higher mean serum PO4 and Ca × PO4 Higher mean PTH levels Higher Ca intake from binders Higher mean calcitriol dose cIMT and CAC correlated with Higher mean PTH levels Higher mean calcitriol dose Mean time-averaged Ca x P cIMT, ECHO, and CAC 9-dialysis – 2.9 ± 3.5 years 31 – transplant 9.2 ± 4.3 years 39-dialysis – 4.9 ± 2.7 years 14 – transplant 3.4 ± 2.7 years PWV correlated with Mean PO4 levels Mean serum Ca × PO4 Age was the only significant predictor of aortic augmentation index cIMT, PWV, and aortic augmentation index 1 month to 6 years (all HD) When mean PTH levels > twofold upper limit of normal increased risk of vascular damage and calcification as compared to those with PTH levels < twofold upper limit of normal Increased cIMT, hs-CRP, and homocysteine levels in patients compared with controls, but no difference in endothelium-dependent dilatation between the groups Endothelium-dependent dilatation correlated with cIMT Increased cIMT, left ventricular hypertrophy, and higher left ventricular mass index in the dialysis as compared to control groups Significant negative correlation between cIMT and PTH CAC was present in of 53 (15%) – currently on dialysis and transplanted PWV and aortic augmentation index significantly higher in patients than controls, and comparable with adult values No reversibility after a dialysis session, suggesting that structural changes underlie the loss of function No difference in cIMT between dialysis patients, transplant recipients, and controls 10% had moderate to severe CAC, and 9% had mild CAC cIMT was higher in patients with calcification 30 The Cardiovascular Status of Pediatric Dialysis Patients 567 R Shroff and M M Mitsnefes 568 a b c Fig 30.2 Surrogate measures of cardiovascular risk in pulse wave velocity Inset shows carotid and femoral CKD patients (a) High-resolution ultrasound of the com- waveforms (c) Multislice CT scan showing coronary mon carotid artery to measure the carotid artery intima- artery calcification (inset) media thickness (cIMT) (b) Tonometry to measure the Diastolic dysfunction is thought to be the initial functional LV abnormality evident in children with CKD. Historically, the most widely used method of assessment of impaired LV relaxation has been the use of Doppler measurement of the mitral inflow velocity (with E/A ratio